Chronic liver injury due to any number of causes such as viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis, cholestatic liver diseae, or metabolic disorders of the liver can lead to development of hepatic fibrosis and cirrhosis. Hepatic fibrosis is a well-known sequela of liver injury that remains a significant challenge to treat. Hepatic fibrosis is a complex process that involves many cell types within the liver including activated myofibroblasts - the source of extracellular matrix and fibrous scar formation. While myofibroblasts are the primary mediators of fibrosis, other cell types including hepatocytes are known to play an important role in promoting hepatic fibrosis during liver injury through the release of cytokines and growth factors to influence myofibroblast activation and proliferation. During the process of liver injury, platelet-derived growth factors (PDGFs) are secreted from numerous resident and infiltrating cell sources and are believed to promote cell survival and expansion through binding to PDGF receptors (PDGFR) including PDGFRa. Evidence from our lab and others suggest that PDGFRa signaling may occur not only in hepatic stellate cells (HSCs), but also within regenerative hepatocytes in models such as partial hepatectomy and carbon tetrachloride (CCl4). The presence of PDGFRa in both proliferating HSCs and hepatocytes suggests that this receptor may have disparate cell-specific roles in the liver injury and fibrosis, where it may promote HSC activation and fibrosis while providing proliferative advantage to hepatocytes. Such a dichotomous relationship needs to be experimentally addressed since therapeutic PDGFRa inhibition may become a reality due to the emergence and success of PDGFRa targeting agents. Indeed, cell-specific studies of PDGFRa designed to assess the role of this receptor in individual cell populations of the liver in vivo ar currently lacking. We hypothesize that PDGFRa plays cell-specific roles in the development of fibrosis, in which PDGFRa signaling in HSCs, but not hepatocytes, is critical and required for hepatic fibrosis. The current proposal will investigate the effect of PDGFRa loss from hepatocytes and HSCs on liver injury, fibrosis and regeneration. In Aim 1, we will study genetic mouse models of chronic or acute PDGFRa loss from hepatocytes that are subjected to bile duct ligation (BDL) or CCl4. This aim will test the hypothesis that PDGFRa loss from hepatocytes will not impact disease based on signaling redundancy. Aim 2 will utilize HSC conditional knockouts of PDGFRa and investigate the impact of PDGFRa loss from this cell type on development of fibrosis after BDL and CCl4. This aim will test the hypothesis that PDGFRa upregulation is indispensable to HSC activation and development of fibrosis. Thus the entire proposal will inform the safety of PDGFRa inhibition in hepatocytes and validate PDGFRa as a therapeutic target in hepatic fibrosis and cirrhosis. In summary, our study will not only elucidate the biology of PDGFRa in hepatic fibrosis in a cell-specific manner, but also address the safety and efficacy of targeting this molecule for a major unmet clinical need: the treatment of hepatic fibrosis and cirrhosis.